For Jean-Laurent Casanova, the question is a simple one: Why do the same germs make some people sicker than others? His 20-year search for answers has led to fundamental new discoveries about how genes influence a variety of infectious diseases.
Jean-Laurent already had a long and illustrious career in France when he received an offer to join The Rockefeller University in 2008. A physician-scientist and immunologist, he had begun to unravel a relationship between genes and infectious disease that would come to change how scientists think of many common illnesses. Indeed, he’d had many offers over the years from American institutions—but Rockefeller’s was the only one he considered accepting. “It is evidence of how much I love and admire this place,” he says.
After receiving his medical degree from the Cochin Medical School at the Paris Descartes University, and a Ph.D. in immunology from the Pierre and Marie Curie University in Paris, Jean-Laurent pursued a career in pediatrics. And it was during his residency at Paris’s Necker Hospital for Sick Children that he made the discovery that would come to define his life’s work.
“We come here with ideas, with a vision, and are given the autonomy to follow our instincts. Rockefeller allows us to do the transformative science that we anticipate will have an enduring impact on the health and well-being of our world.”
Frustration with vaccinations
In the summer of 1994, Jean-Laurent became intrigued with reports in the medical literature of healthy children who had suddenly become extremely ill after receiving vaccinations against tuberculosis made with disseminated bacteria called Bacille Calmette-Guérin.
Acting on a hunch that the children might be genetically predisposed to developing such infections, he rifled off letters to hundreds of pediatricians around France, asking that they send him their case reports. One letter in particular detailed the case of a four-year-old girl who had experienced a baffling array of life-threatening symptoms after receiving the tuberculosis vaccination. He embarked on an in-depth study of her case, and six years later revealed the genetic basis of her illness: a mutation in a protein called STAT1, which activates genes involved in the body’s immune response to mycobacteria. So began a career studying inborn errors of immunity.
Unraveling an enigma
“Everyone has suffered from infectious disease, be it influenza or chicken pox,” Jean-Laurent says. “What we do is test the hypothesis that severe infectious disease is not merely infectious but also results from a genetic variation or mutation that is within a person when he or she is born.” Most people who get the flu stay in bed for a few days, but one percent or so end up in the hospital. “It’s the same microbe, so how do we account for the difference?” Jean-Laurent asks.
Over the past two decades, Jean-Laurent and his colleagues have discovered single-gene (monogenic) inborn errors of immunity in children that confer severe and selective vulnerability to specific infectious illnesses including tuberculosis, pneumococcal disease, herpes simplex, encephalitis, and Candida infection.
Revealing monogenic “holes” in the immune defense of otherwise healthy children has important clinical implications. “Eventually, it may provide pediatricians with the means to predict which children are vulnerable to which infections,” says Jean-Laurent. This would offer families the possibility for diagnosis and genetic counseling as well as treatments aimed at restoring an immune response.
Among other projects, Jean-Laurent’s laboratory is currently exploring why some individuals who carry a congenital mutation do not develop clinical illness. It is also trying to define the level of genetic heterogeneity, or the number of genes that are mutated in a group of patients with a particular infectious disease. This work is made possible by the group’s access to The Rockefeller University Hospital, a one-of-a-kind facility dedicated exclusively to clinical research, where Jean-Laurent is the primary investigator on some half-dozen active clinical research trials.
“Rockefeller is an extraordinary institution that is run in a unique way,” says Jean-Laurent, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Diseases as well as a Howard Hughes Medical Institute investigator. “We have no departments, no barriers to exploration. It’s all about the science. At Rockefeller, I’ve been able to do the research I have dreamt of and follow it wherever it leads.”